This proposal will be a critical appraisal of the quantitative techniques that are available to study dopamine D1 and D2 receptors in schizophrenia and matched control subjects. Over the last 2 years we have been developing Positron Emission Tomography (PET) techniques for studying these receptors in vivo and have recently developed more and more sophisticated models and physics considerations for quantitation of absolute receptor densities. Our preliminary studies with the current state of our quantitative technique have shown striking two to three fold increases of receptor densities in both drug-naive and drug- treated schizophrenic patients as compared to matched controls. However, a detailed and rigorous examination of these models has not been completed and in view of the preliminary results are essential to future study of schisophrenia. A number of the assumptions made in our current models, although reasonable, must be validated in detail. Furthermore, alternative procedures for quantification must also be considered in the light of the resources in our institution. This grant application will examine in detail the analysis methods in all aspects of the quantitative imaging of D2 and D1 receptors with 11C-NMSP and 11C- SCH23390 respectively including the chemical, physical, physiological, mathematical modeling which is available to apply to our schizophrenic populations which are being studied. With the completion of this project we will be in an even stronger position to apply these quantitative methods to further schizophrenia research in areas such as high risk population for schizophrenia and the study of the relationship between therapy and receptor occupancy for better therapeutic monitoring. Our long range goals are thus to validate and improve our quantification of dopamine receptors in living human brain and to apply this to schizophrenic subjects for both absolute densities measures as well as occupancy measures as a function of therapy and clinical course.